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Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [¹¹C]NNC112.

ABSTRACT: Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder.The aim of this study was to characterize prefrontal D1 receptor availability and its relation to WM performance in SPD.We used positron emission tomography (PET) and the radiotracer [(11)C]NNC112 with 18 unmedicated SPD and 21 healthy control participants; as an index of D1 receptor availability, binding potential (BP) measures (BPF, BPND, and BPP) were calculated for prefrontal and striatal subregions. To assess WM, SPD participants completed the 2-back and Paced Auditory Serial Addition Test (PASAT).There were no significant group differences in PFC BP. BPF and BPP in the medial PFC were significantly negatively related to PASAT performance (r s ?=?-0.551, p?=?.022 and r s ?=?-0.488, p?=?.047, respectively), but BP was not related to 2-back performance.In contrast to what has been found in schizophrenia, SPD was not associated with significant alterations in prefrontal D1 receptor availability. Similar to previous schizophrenia findings, however, higher prefrontal D1 receptor availability was associated with poorer WM performance (as measured by the PASAT) in SPD. These findings suggest that schizophrenia and SPD may share a common pathophysiological feature related to prefrontal dopamine functioning that contributes to WM dysfunction, but that in SPD, alterations in D1 may occur only in a subset of individuals and/or to an extent that is minor relative to what occurs in schizophrenia.

SUBMITTER: Thompson JL

PROVIDER: S-EPMC4194223 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [¹¹C]NNC112.

Thompson Judy L JL Rosell Daniel R DR Slifstein Mark M Girgis Ragy R RR Xu Xiaoyan X Ehrlich Yosefa Y Kegeles Lawrence S LS Hazlett Erin A EA Abi-Dargham Anissa A Siever Larry J LJ

Psychopharmacology 20140430 21

<h4>Rationale</h4>Schizotypal personality disorder (SPD) is associated with working memory (WM) impairments that are similar to those observed in schizophrenia. Imaging studies have suggested that schizophrenia is associated with alterations in dopamine D1 receptor availability in the prefrontal cortex (PFC) that may be related to the WM impairments that characterize this disorder.<h4>Objectives</h4>The aim of this study was to characterize prefrontal D1 receptor availability and its relation to ...[more]

PMID: 24781514

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Project description:Pharmacological enhancement of prefrontal D1 dopamine receptor function remains a promising therapeutic approach to ameliorate schizophrenia-spectrum working memory deficits, but has yet to be rigorously evaluated clinically. This proof-of-principle study sought to determine whether the active enantiomer of the selective and full D1 receptor agonist dihydrexidine (DAR-0100A) could attenuate working memory impairments in unmedicated patients with schizotypal personality disorder (SPD). We performed a randomized, double-blind, placebo-controlled trial of DAR-0100A (15 mg/150 ml of normal saline administered intravenously over 30 min) in medication-free patients with SPD (n=16) who met the criteria for cognitive impairment (ie, scoring below the 25th percentile on tests of working memory). We employed two measures of verbal working memory that are salient to schizophrenia-spectrum cognitive deficits, and that clinical data implicate as being associated with prefrontal D1 availability: (1) the Paced Auditory Serial Addition Test (PASAT); and (2) the N-back test (ratio of 2-back:0-back scores). Study procedures occurred over four consecutive days, with working memory testing on Days 1 and 4, and DAR-0100A/placebo administration on Days 2-4. Treatment with DAR-0100A was associated with significantly improved PASAT performance relative to placebo, with a very large effect size (Cohen's d=1.14). Performance on the N-back ratio was also significantly improved; however, this effect rested on both a non-significant enhancement and diminution of 2-back and 0-back performance, respectively; therefore interpretation of this finding is more complicated. DAR-0100A was generally well tolerated, with no serious medical or psychiatric adverse events; common side effects were mild to moderate and transient, consisting mainly of sedation, lightheadedness, tachycardia, and hypotension; however, we were able to minimize these effects, without altering the dose, with supportive measures, eg, co-administered normal saline. Although preliminary, these findings lend further clinical support to the potential of D1 receptor agonists to treat schizophrenia-spectrum working memory impairments. These data suggest a need for further studies with larger group sizes, serum DAR-0100A levels, and a more comprehensive neuropsychological battery.

Dataset Information

Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [¹¹C]NNC112.

Publications

Prefrontal dopamine D1 receptors and working memory in schizotypal personality disorder: a PET study with [¹¹C]NNC112.

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